Objectives The objective of the lecture is to discuss the benign and malignant neoplasms of the small and large intestine. Learning Outcomes At the end of the lecture, students should be able to: 27.1 Discuss the etiology and morphology of intestinal ischemia 27.2 List the tumours of the intestine 27.3 Discuss the classification, morphology, and clinical presentation of polyps and adenomas 27.4 Discuss the concept of colorectal carcinogenesis in terms of the adenoma-carcinoma sequence and molecular basis Discuss the epidemiology, etiology, morphology, clinical presentation and complications of colorectal cancers

Intestinal Ischaemia Def:- acute or chronic loss of blood supply to a part of small or large intestine. Aetiology 1.Arterial thrombosis Atherosclerosis vasculitis Angiographic procedures Oral contraceptive

2.Arterial Embolism Cardiac vegetation Mural thrombi with MI Aortic Athero-embolism 3.Venous thrombosis Hypercoagulable state induced by ATIII Def, oral contraceptive therapy,Post operative state and other causes

4.Non-occlusive Ischaemia:- cardiac failure shock dehydration vasoconstrictive drugs 5. Miscellaneous causes volvulus & strangulation stricture Hernial sac obstruction

Morphology Transmural Intestinal Infarction:- Gross:- affected segment is dark red,haemorrhagic and covered by a thin fibrinous exudate over serosa. In arterial occlusion margins of infarct are sharply defined ; In venous oclusion margins less distinct Micro- -Ischaemic necrosis with oedema haemorrhage necrosis and later on sloughing of mucosa. After 24 hrs intestinal bacteria will lead to gangrene and later perforation

Mucosal and Mural infarction GROSS:- Multifocal lesions with in between spared areas Mucosa is thickened,haemorrhagic and oedematous with superficial ulceration Micro-- Ischaemic necrosis confined to mucosa and submucosa Pseudomembrane formation on surface due to inflammatory Fibrin containing exudate secondary to bact. Infection

Small Int.Infarction

Volvulous Caecum

Ischaemic Enteritis Small Intestine(SHOCK)

Normal Mucosa Small Int.

Necrosis Mucosa and Submucosa

Tumours Of Small And Large Intestine (Classification) Non-neoplastic Polyps Hyperplastic polyps Hamartomatous polyps Juvenile Polyps Inflammatory polyps Lymphoid polyps Neoplastic polyp orEpithelial Lesions Benign Adenomas Malignant Adenocarcinoma Squamous cell carcinoma of the anus Others Gastrointestinal stromal tumors(GIST) Carcinoid tumor* Lymphoma*,leiomyoma and leiomyosarcoma* Secondary*

Intestinal Polyp Definition:-is a mass that protrudes from surface mucosa in lumen of gut. Polyps are most common in the colon but may occur in the esophagus, stomach, or small intestine.

Intestinal Polyp-Classification Two Types sessile, without a stalk. pedunculated. Polyps with stalks can also be classified as Non-neoplastic Inflammatory Hamartomatous Juvenile polyp Hyperplastic

Neoplastic Benign- Adenoma or adenomatous polyp Tubular Villous Tubulo-Villous Sessile-Serrated Malignant-carcinoma

Inherited Polyposis Syndromes Familial Adenomatous Polyposis(FAP) Peutz- Jegher Syndrome Juvenile Polyposis Syndrome

Tumors of the Colon and Rectum Non-neoplastic Polyps,-formed due abnormal mucosal maturation,inflammation and abnormal architecture. No cancer risk

Hyperplastic Polyp 90% in large intestine,most common in rectum Age- above 60 yrs. Gross:- Small,<5 mm,nipple like protrusion of mucosa. single or multiple. Micro:-Abundant serrated crypts lined by goblets cells,seperated by scant lamina propria.No malignant Potential. As part of hyperplastic polyposis syndrome- Malignant potential

Hyperplastic Polyp

Hamartomatous or juvenile polyp Tumour like growth due to faulty development Most common in children < 5 yrs of age usually solitary called juvenile polyp. In adults called retention polyp 1-3cm in diameter,rounded smooth or lobulated,occur singly in rectum;stalk sometimes 2 cm long. Hamartomatous proliferation in lamina propria enclosing widely spaced cystic glands..No malignant potential Multiple hamartomatous polyps are found as part of Peutz Jegher Syndrome Or juvenile multiple polyposis syndrome.

Juvenile Polyp

Inflammatory( Pseudo)Polyp Associated with inflammatory conditions –Ulcerative Colitis,Crohn’s disease,amoebic colitis Inflammed regenerating mucosa surronded by ulcerated tissue or granulation tissue with overlying epithelium. Gross:-smooth hypervascular appearance Micro:-inflammed lamina propria.distorted colonic glands(branched,tortuous and cystic). congestion,haemorrhage and granulation tissue

Ulcerative Colitis

Pseudo polyps

INFL. Polyp

Inflammatory Polyp

Adenomatous polyp or Adenoma The most common and clinically important neoplastic polyps are colonic adenomas(adenomatous Polyp) --benign polyps that are precursors to the majority of colorectal adenocarcinomas.

Adenomatous Polyp(Tubular adenomas) Most common in adults called tubular because of rounded nature of neoplastic glands Mostly are pedunculated 50 % found rectum & sigmoid colon. Majority are small 1cm.Large one(2.5 cm and above) have a 1-2 cm stalk Surface rasberry like. Head is composed of neoplastic epithelium forming branching glands lined by tall hyperchromatic cells. Mucin secretion +or - Always benign except when larger than 2cm carry greater risk

Adenomatous Polyp(tubular Adenoma)

Adenomatous Polyp with long stalk

Colonic adenoma A.pedunculated(endoscopic view)B.Adenoma with velvety surfaceC.Low magnification pedunculated adenoma

Tubular adenoma

Normal mucosa (left) Tubular adenoma(Rt)

Villous adenomas Most common in rectum &sigmoid colon. Occurs in old age Often large & sessile High Ca risk. If > 4cm-- cancer risk upto 40%. Gross- -Sessile cauliflower like mass projecting 1- 3cm above normal mucosa. Micro -villiform frond like projecton lined by dysplastic epithelial cells.Invasive ca found in upto 40%.

Endoscopy-villous adenoma

Villous Adenoma

GI Pathology Villous Adenoma - photomicrograph

Tubulo-Villous adenomas. Mixture of tubules & villi. Intermediate Ca risk-

Familial polyposis syndrome

Clinical Features-Polyps Most patient no symptoms Abdominal pain(rare) Most common symptom rectal bleeding Occult bleeding in some patient Other symptoms include Diarrhoea constipaion or change in bowel habits. Chronic bleeding may cause weakness,fatigue and iron def. anaemia.

Carcinoma of colon

Epdemiology Leading cause of cancer death in USA.3rd most commonly diagnosed ca in males Highest incidence in Australia and Newzeland :lowest in Africa and South Centaal Asia due to dietary habits Males.>Females Peak age-60-79yrs If found in younger person, HNPCC(hereditary nonpolyposis colorectal cancer syndrome) or Ulcerative Colitis have to be suspected Almost all colon cancer begin in noncancerous polyp Smoking,alcohol,diets,physical inactivity and obesity.

Risk Factors Age > 50 yrs Over weight Sedentary lifestyle Smoking and Alcohol Inflammatory conditions DIET Family history and inheritance Adenomatous Polyps and Polyposis syndromes

ETIOLOGY Diet & colonic cancer Excess energy intake relative to requirement Low unabsorbable fiber content High content of refined carbohydrates High Intake red meat Decrease intake of protective micronutrients (particularly vitamin A, C & E)

These factors Lead to decreased stool bulk, increased fecal transit time(constipation) & altered bacterial flora of the bowel Toxic oxidative by-product of carbohydrate by bacteria are held in contact of mucosa for a longer period due to constipation.

ETIOLOGY (contd) Cyclo-oxygenase(COX 2 ) Are found in higher conc. in all ca of colon & 90% of adenoma. Mechanism not known. PGE2 causes epithelial proliferation & inhibits apoptosis.Aspirin is protective. Genetic factors Inherited and acquired mutation in several genes are associated with colon carcinoma. APC.DCC,K- RAS.P53,DNA REPAIR GENES

Colorectal Carcinogenesis CA COLON is an example of multi step carcinogenesis. Molecular events that lead to colonic carcinoma include genetic and epigenetic abnormality. Carcinomas arise from accumulation of activation of oncogenes and inactivation of tumour suppessor genes that initially cause adenomatous polyp:then acquire additional mutation and become malignant(4-10 mutations are required to produce malignant phenotype)

GENETIC PATHWAY Two distinct genetic Pathways have been described 1.Classic adenoma-carcinoma sequence/ Chromosomal Instability Pathway/APC-beta catenin pathway. (Abnormal number of chromosomes - aneuploidy or gain or loss of chromosomal regions)

2.microsatellite instability pathway/DNA mismatch repair gene alteration

Both pathway involve stepwise accumulation of multiple mutations but gene involved and mechanism is different.

Epigenetic events Most common type is methylation induced gene silencing. May enhance progression along both pathway.

Adenoma-Carcinoma sequence Most cancers believed to arise within pre- existing adenomas Risk of cancer greatest in villous adenoma Series of mutations results in epithelial changes from normal through hyperplasia to neoplasia(adenoma) to dysplasia to carcinoma to invasion Important genes - APC, DCC, k-ras, p53. DNA repair genes

Adenoma carcinoma Sequence APC is tumour suppressor gene.It promotes degradation of B- catenin which is a messenger protein in WNT signal transduction pathway.Loss of APC function due to mutation leads to accumulation & translocation of B-CATENIN to nucleus where it activates transcription of several genes-MYC & CYCLIN D1 which promotes cell proliferation. 80% of sporadic colon carcinoma have APC mutation

Adenoma-Carcinoma sequence Mutation of APC gene occurs early in nepoplastic process. Both copies of APC must be inactivated either by mutaion or epigenetic events.This leads to develoment of Adenoma. Neoplastic progression is associated with Additional mutations in K-RAS which promotes growth and prevents apoptosis.Mutation in other tumour suppression genes such as DCC, SMAD4 And P53. Loss of these genes allowes unrestricted cell growth

Adenoma-Carcinoma Sequence

Microsatellite instability pathway(MSI) Inactivation of DNA mismatch repair genes which leads to mutation accumulation. Inherited mutation in one of several DNA Mismatch Repair gene such as MSH2 & MLH1 give rise to Hereditary Non Polyposis Colon Cancer (HNPCC) In Sporadic colon cancer MSI is usually caused by loss of expression of MLH1 secondary to Its Promoter region methylation % of colonic cancer have MSI

Colon carcinogenesis

MORPHOLOGY

Carcinoma Colon

Distribution of colonic cancerSiteProportion Cecum / ascending colon 25% Descending colon / prox sigmoid 25% Rectum and distal Sigmoid 25% Remaining sites Remaining sites25%

Carcinoma of colon GROSS:- Tumors of the proximal colon are usually polypoid exophytic growths extend along the wall of caecum and ascending colon Tumors of the distal colon tend to be annular encircling lesions (napkin ring cancers)causing contraction of bowel and narrowing of lumen Both invade and can form mass on serosal surface

Micro:- Adenocarcinoma(forming glands) well to undiffertiated Mucinous carcinoma - produce too much mucin Signet ring cell ca-more than 50% cells are signet ring cells Cancer of anal region-squamous cell ca

Clinical Presentation Initially no symptoms Abdominal bloating,pain,cramps and gas Change in bowel habits Feeling bowel has not emptied Ribbon like stools Blood in stools Weight loss of unexplained nature Weakness and fatigue

Unexplained Iron def anaemia Unexplained nausea and vomiting Exam- lump abdomen Recal mass Fecal occult blood colonoscopy

Complications Intestinal obstruction – more common on left side GIT haemorrhage Perforation,infection and abscess formation Metastasis Recurrence after surgery Development of second primary from other site- metachronosis Side effects of surgery,radio and chemo

Adenocarcinoma of the colon

Adenocarcinoma of the colon - “napkin ring”

Exophytic Growth

Colon Ca-Gland formation

Adenocarcinoma of the colon (Mucicarmine)

GI Pathology Adenocarcinoma of the colon (Micro)

Moderately DiFF.CA Colon showing Necrosis

Mucinous Carcinoma

Signet ring cell carcinoma

Carcinoid Found in the fore-, mid- and hindgut Appendix (20%) & ileum (2%)- most common sites All have potential for malignant behavior Malignant carcinoid tumor may replace the hepatic parenchyma, leading to the “carcinoid syndrome” Functional - increased serotonin leading to carcinoid heart disease

CARCINOID “Carcinoma like”-arises from endocrine cells secreting peptide & non peptide hormone along GIT mucosa.Potentially malignant but appendicular & rectal almost never. Gross-solid, yellow tan on transection cause excessive desmoplasia leading to kinking. Micro-neoplastic cells form descrete islands, trabeculae,ribbon like,or glands or undiffrentiated.Tumour cells are monotonous with pink granular cytoplasm.Round to oval nucleus with ‘ salt- pepper’ chromatin

Carcinoid syndrome Vasomotor disturbance. Cutaneous flushes Intestinal Hypermotility-diarrhea cramps,nausea. Asthamatic-cough,heesing etc Systemic fibrosis Cardiac-pulm. Tricuspid stenosis All changes due to production of vasoactive amines( HT, 5HIAA)

GI Pathology Carcinoid of Appendix - Gross

Carcinoid small intestine

Carcinoid